When Jingkun Zeng, PhD, joined the lab of Nobel laureate, Jennifer Doudna, PhD, as a postdoctoral researcher in 2024, he was not interested in applying CRISPR for gene editing.

The molecular scissors had demonstrated extraordinary clinical promise in correcting single-point mutations, most strikingly in Baby KJ’s case, where a rare metabolic disorder once presented a 50% mortality rate in infancy.  

Yet, Zeng had his ambitious sights on stopping cancer progression, where the biology “became messy.” Cancer can be driven by hundreds of thousands of mutations, making it nearly impossible to correct each mutation one-by-one to restore healthy function. 

Zeng, who completed his PhD training in cancer evolution at The Francis Crick Institute, aimed to develop new CRISPR-based technology that could therapeutically access the undruggable tumor suppressor protein, p53. Mutations in this “guardian of the genome” are found in nearly half of all cancers, and up to 70–90% of cases of the most deadly tumors, including ovarian, pancreatic, and non-small cell lung cancer. 

In a new study published in Nature titled, “Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding,” Zeng and colleagues from Innovative Genomics Institute (IGI), University of California (UC) Berkeley, UC San Francisco (UCSF), and Gladstone Institutes, have now engineered a CRISPR system to selectively trigger cancer cell death by chromatin shredding. 

The approach recognizes cancer cells using the RNA-guided nuclease, CRISPR-Cas12a2, to recognize mutant p53 mRNA transcripts. Therapeutic effectiveness was demonstrated in mouse models of lung and liver tumors. 

Bacterial roots 

Mutations in p53 are early drivers in the cancer-causing cascade, making the tumor suppressor one of the most sought-after targets in cancer therapy. Yet despite decades of effort, no approved p53 drugs exist on the market. 

Unlike many druggable proteins, p53 lacks a well-defined binding pocket traditionally required by established modalities, such as small molecules or antibodies. Additionally, most cancer therapeutics are designed to inhibit disease-driving proteins, whereas restoring p53 function demands precise, controlled activation of a tumor suppressor. 

“It’s the first time we managed to target p53 with such precision,” Zeng told GEN, emphasizing that CRISPR-Cas12a2 can distinguish healthy and disease cells that differed by just one nucleotide.

The novel drug modality takes advantage of CRISPR’s bacterial roots as a defense system that protects against infection by cutting the genetic material of invading viruses, preventing replication and spread.

Zeng also emphasizes that the guide RNA is easily programmable for additional therapeutic areas, such as destroying viral infected cells or abnormal cells due to aging. The technology can also be multiplexed to recognize multiple cancer mutations simultaneously.

The work joins a growing industry effort to develop scalable and generalizable genetic medicines. 

Looking ahead, the authors aim to improve the delivery efficiency to cancer cells, a longstanding challenge across CRISPR therapies. The team is also undergoing collaborations to apply the technology across diverse cancer types, including brain, prostate, and ovarian cancer. 

The post CRISPR Shreds Undruggable Cancer Cells with Precision appeared first on GEN – Genetic Engineering and Biotechnology News.